The overall goal of this application is to develop novel protein-based MRI approaches and to demonstrate their potential to resolve the diagnostic dilemma of treatment effects in neuro-oncology. Radiation therapy is a key modality for the treatment of malignant brain tumors, and radiation necrosis is a major complication of radiation therapy. The inability of currently available MRI techniques to differentiate tumor progression from radiation necrosis after brain tumor therapy complicates daily patient care, and is a critical barrier to investigating the efficacy of new therapies for brain tumors. Recently, we have designed a new molecular MRI technique, dubbed amide proton transfer (APT) imaging, which detects amide protons of endogenous mobile proteins and peptides in tissue. Our preliminary data in preclinical models demonstrate that APT imaging provides a unique signal in untreated glioma (hyperintense relative to normal and normal-appearing contralateral tissue), compared to pure radiation necrosis (hypointense or isointense). The specific aims of this proposal are: (i) Optimize our protein-based MRI techniques and determine their accuracy in distinguishing radiation necrosis from tumor recurrence and (ii) Evaluate whether APT-MRI signal is an early biomarker to predict tumor response and animal survival. To achieve our goal, we have assembled a multidisciplinary team of basic scientists and clinicians. The results of this preclinical study will provide the first accuracy data for a new imaging biomarker for identifying tumor progression versus radiation necrosis, and for the prediction the efficacy of radiation therapy in malignant gliomas. These data are needed for a further study in clinical populations.